Process for converting a polymeric ester to a polymeric acid

ABSTRACT

The present invention generally relates to processes for converting an ester group to an acid group for polymers having a pendant ester of an acid group. This process is generally performed using an aqueous strong base.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Nonprovisional patentapplication Ser. No. 15/276,175 filed on Sep. 26, 2016, which is acontinuation of U.S. Nonprovisional patent application Ser. No.14/128,852 filed on Feb. 4, 2014 (U.S. Pat. No. 9,453,092), which is aU.S. 371 National Patent Application of PCT/US2012/044404 filed on Jun.27, 2012, which claims the benefit of U.S. Provisional PatentApplication No. 61/501,625, filed on Jun. 27, 2011.

FIELD OF THE INVENTION

The present invention generally relates to processes for converting anester group to an acid group for polymers having a pendant ester of anacid group. This process is generally performed using an aqueous strongbase.

BACKGROUND OF THE INVENTION

It is generally known that hyperkalemia can be treated with variouscation exchange polymers including polyfluoroacrylic acid (polyFAA) asdisclosed in WO 2005/097081, WO 2010/022381, WO 2010/022382, and WO2010/022383, each of which is incorporated herein in their entirety byreference.

In the previous methods of manufacturing these polymers, however, longerreaction times under atmospheric air were used. Such processes are notsuited to commercial production due to increased costs and the presenceof impurities. It has been found that when polymers are hydrolyzed in abead form, it is difficult to completely hydrolyze the ester groups toacids groups because it is difficult to hydrolyze the ester groups onthe inside of the bead.

SUMMARY OF THE INVENTION

The present invention provides a process for converting an ester groupof a polymer to an acid group by forming a reaction mixture comprisingan aqueous strong base solution and a polymer having a pendant ester ofan acid group, wherein the reaction mixture either (i) has asubstantially inert atmosphere, (ii) is allowed to react for up to 14hours, and/or (iii) contains at least 1 kg of a polymer having a pendantester of an acid group. An additional aspect is where the polymer is ina bead form.

One of the many aspects of the invention is a process for converting anester group of a polymer to an acid group. The process comprises forminga reaction mixture having a substantially inert atmosphere wherein thereaction mixture comprises an aqueous strong base solution and a polymerhaving a pendant ester of an acid group which hydrolyzes to produce apolymer comprising the pendant acid group or a salt thereof and analcohol.

Another aspect is a process for converting an ester group of a polymerto an acid group that comprises forming a reaction mixture, the reactionmixture comprising an aqueous strong base solution and a polymer havinga pendant ester of an acid group which hydrolyzes to produce a polymercomprising the pendant acid group or a salt thereof and an alcohol,wherein the reaction mixture is allowed to react for up to 14 hours.

Yet another aspect is a process for converting an ester group of apolymer to an acid group that comprises forming a reaction mixture, thereaction mixture comprising an aqueous strong base solution and at least1 kg of a polymer having a pendant ester of an acid group whichhydrolyzes to produce a polymer comprising the pendant acid group or asalt thereof and an alcohol.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Polymers having a pendant ester group can be more difficult to convertto acid groups by hydrolysis with an aqueous base because of the stericeffects of the ester group being attached to a polymer backbone. Thepolymer having a pendant ester group is in the form of a bead and theester groups attached to the polymer on the inside of the bead are moredifficult to convert to acid groups than the ester groups on the outsideof the bead. Further, the process described herein provides an improvedway to control the cation exchange capacity of the product polymerhaving a pendant acid group by closely controlling the conversion of thepolymer having a pendant ester of an acid group to the polymer having apendant acid group.

Further, it has been discovered that the presence of oxygen in thereaction can cause impurities in the polymer having an acid group uponhydrolysis of the polymer having a pendant ester of an acid group. Ithas also been found that a relatively long reaction time along withexposure to high temperatures can also result in more impurities in thepolymer having an acid group. When the hydrolysis reaction is performedas a larger scale reaction, more impurities resulted in the productpolymer. The presence of impurities can be minimized in the resultingpolymer, even when the polymer is produced in kilogram scale quantities,by performing the hydrolysis reaction with an aqueous strong basesolution in a substantially oxygen-free (e.g., inert) atmosphere and/orby decreasing the reaction time. The hydrolysis process described hereinprovides a polymer having a pendant acid group that has a moreconsistent color and minimizes the color differences between polymerlots.

The polymer having a pendant ester group can undergo a reaction with anaqueous strong base where the ester group is converted to an acid groupand an alcohol is produced. Generally this reaction is described asfollows:

wherein R is a hydrocarbyl group such as alkyl and M⁺ is a monovalentcation. M⁺ can be selected from the group of H⁺, Li⁺, Na⁺, K⁺, Rb⁺, Cs⁺,Ca²⁺, Sr²⁺, Ba²⁺, or a combination thereof. In various preferredreactions, M⁺ is H⁺, Ca²⁺, or a combination thereof. The reaction occurson the pendant ester group that is attached to the polymer; the polymerattachment occurs at the wavy bond.

The polymer having a pendant ester group can be a hydrophobic polymer.This hydrophobic polymer tends to repel, not combine with, or notdissolve in water. Thus, since the aqueous base solution contains water,the hydrolysis of hydrophobic polymers is more difficult due to thistendency to repel, not combine with, or not dissolve in water.

The acid group can be a carboxylic acid group, a phosphonic acid group,a phosphoric acid group, a sulfonic acid group, a sulfuric acid group, asulfamic acid group, or a salt thereof. Preferably, the acid group is acarboxylic acid group.

The hydrophobic polymer having a pendant ester of an acid groupcomprises a methyl ester of poly-α-fluoroacrylic acid. Preferably, themethyl ester of poly-α-fluoroacrylic acid is crosslinked with acrosslinking monomer.

When the methyl ester of poly-α-fluoroacrylic acid is crosslinked with acrosslinking monomer, the crosslinking monomer is preferably divinylbenzene, 1,7-octadiene, or a combination thereof.

The crosslinked hydrophobic polymer having a pendant ester of an acidgroup can comprise structural units corresponding to Formulae 1 and 2,Formulae 1 and 3, or Formulae 1, 2, and 3, wherein Formula 1, Formula 2,and Formula 3 are represented by the following structures:

wherein R₁ and R₂ are each independently hydrogen, alkyl, cycloalkyl, oraryl; A₃₁ is an ester of a carboxylic, phosphonic, or phosphoric group;X₁ is arylene; and X₂ is alkylene, an ether moiety, or an amide moiety.

In some of the preferred embodiments, the crosslinked hydrophobicpolymer is represented by Formulae 1A, 2A, and 3A:

The polymer having a pendant ester of an acid group can comprise areaction product of a polymerization mixture comprising monomers ofeither (i) Formulae 11 and 22, (ii) Formulae 11 and 33, or (iii)Formulae 11, 22, and 33, wherein Formula 11, Formula 22, and Formula 33are represented by the following structures:

and wherein R₁ and R₂ are each independently hydrogen, alkyl,cycloalkyl, or aryl; A₃₁ is an ester of a carboxylic, phosphonic, orphosphoric acid group; X₁ is arylene; and X₂ is alkylene, an ethermoiety, or an amide moiety.

A preferred polymer can comprise a reaction product of a polymerizationmixture comprising monomers of Formulae 11A, 22A, and 33A:

The alkyl group of the ester comprises methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 2-pentyl,3-pentyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 3-methyl-2-butyl,2,2-dimethyl-1-propyl, 1,1-dimethyl-1-propyl, n-hexyl, 2-hexyl, 3-hexyl,2-methyl-1-pentyl, 2-methyl-2-pentyl, 2-methyl-3-pentyl,3-methyl-1-pentyl, 3-methyl-2-pentyl, 3-methyl-3-pentyl,4-methyl-1-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl,2,3-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 3,3-dimethyl-2-butyl,2,3-dimethyl-2-butyl, or 2-ethyl-1-butyl ester. Preferably, the alkylgroup of the ester is methyl.

For the process of this invention, the reaction mixture can be anaqueous suspension comprising the polymer having a pendant ester of anacid group and an aqueous base solution. In this aqueous suspension, thesolids content of the polymer having a pendant ester of an acid group isfrom about 15 wt. % to about 30 wt. %; preferably, 20 wt. % to about 30wt. %; more preferably, 20 wt. % based on the total amount of polymer inthe suspension.

The product polymer comprising an acid group or a salt thereof cancomprise structural units corresponding to Formulae 15 and 25, Formulae15 and 35, or Formulae 15, 25, and 35, wherein Formula 15, Formula 25,and Formula 35 are represented by the following structures:

wherein R₁ and R₂ are each independently hydrogen, alkyl, cycloalkyl, oraryl; A₄₁ is a carboxylic, phosphonic, or phosphoric group; X₁ isarylene; and X₂ is alkylene, an ether moiety, or an amide moiety.

Preferably, the product polymer having an acid group is represented bystructural units corresponding to Formulae 15A, 25A, and 35A:

As described above, the polymer having a pendant ester of an acid groupis reacted with an aqueous strong base to form the polymer having apendant acid group. The aqueous strong base can be lithium hydroxide,sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesiumhydroxide, calcium hydroxide, strontium hydroxide, barium hydroxide, ora combination thereof. Preferably, the aqueous strong base is sodiumhydroxide, potassium hydroxide, or a combination thereof morepreferably, the aqueous strong base comprises sodium hydroxide.

The concentration of the aqueous strong base solution can range fromabout 15 wt. % to 50 wt. %; preferably, 20 wt. % to about 30 wt. %. Morepreferably, the concentration of the aqueous strong base solution isabout 25 wt. %. The concentration of the aqueous strong base solutioncan also be expressed in units of mole percent; for example, theconcentration of the aqueous strong base solution can range from about10 mole % to about 20 mole %. Preferably, the concentration of theaqueous strong base solution is about 15 mole %.

The molar ratio of the strong base solution to the polymer having apendant ester of an acid group is from about 0.8 to about 1.5;preferably, the ratio is about 1.22.

There are various methods for determining the molar ratio of the strongbase to the polymer having a pendant ester of an acid group. In thefirst method, the strong base (e.g., NaOH) molar equivalent iscalculated by only considering the amount of polymer having a pendantester of an acid group (e.g., methyl ester of poly-α-fluoroacrylate).This calculation results in a molar ratio of NaOH to methyl ester ofpoly-α-fluoroacrylate of 1.22. The second method calculates the molarratio of base (e.g., NaOH) by assuming the starting polymer compositionis the same as the amount of the monomer having a pendant ester of anacid group (e.g., methyl ester of poly-α-fluoroacrylate) that was addedto the polymerization reaction mixture to make the polymer having apendant ester of an acid group. Since the α-fluoroacrylate, methyl estercomprises 89 wt. % of the reaction mixture, the molar ratio of NaOH tomethyl ester of poly-α-fluoroacrylate is 1.086:1.

The strong base solution can further comprise alcohol. The alcohol canbe methanol, ethanol, propanol, or a combination thereof; preferably,the alcohol comprises methanol.

The concentration of the alcohol in the aqueous base solution can befrom about 5 wt. % to about 25 wt. % of the total base solution mass;preferably, the alcohol concentration can be about 10 wt. %.

The reaction solution can further comprise alcohol. The alcohol can bemethanol, ethanol, propanol, or a combination thereof; preferably, thealcohol comprises methanol.

The concentration of the alcohol in the aqueous reaction solution can befrom 5 wt. % to about 15 wt. % based on the final total reaction massafter the addition of base solution; preferably, the alcoholconcentration can be about 7 wt. %.

The atmosphere of the reaction mixture can be a substantiallyoxygen-free or inert atmosphere. The substantially inert atmosphere hasa concentration of oxygen of less than about 5 ppm. The substantiallyinert atmosphere of the reaction mixture is provided by purging theaqueous base solution with an inert gas before adding it to the reactionmixture. The polymer suspension can also be purged with an inert gasbefore the aqueous base solution is added to the polymer suspension. Theinert gas can be helium, neon, nitrogen, argon, krypton, xenon, or acombination thereof; preferably, the inert gas is nitrogen, argon, or acombination thereof.

The reaction time can be up to about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13 or 14 hours. In preferred processes, the reaction time can be up to 5hours. The reaction time can be optimized by measuring the concentrationof sodium ion in the beads and the amount of sodium ion consumed pergram of polymer in the reaction mixture.

The reaction mixture can contain at least about 1 kg, at least about 5kg, at least about 10 kg, or more of the polymer having a pendant esterof an acid group.

The reaction temperature can range from about 55° C. to refluxtemperature (e.g., 85° C.); preferably, from about 80° C. to about 85°C. The reaction mixture can be heated to about 83° C. and the aqueousstrong base can be added over from about 1 hour to about 3 hours;preferably, over about 2 hours. Once the addition of the aqueous strongbase is complete, the reaction mixture is heated for at least 2additional hours at from about 80° C. to about 85° C.; preferably, atabout 83° C. The reaction mixture can be heated for at least 3, at least4, or at least 5 additional hours. The reaction mixture can be cooled toabout 60° C. and if the concentration of sodium ion in the liquid partof the reaction mixture is less than or equal to 3 wt. %, the reactionis complete. Alternatively, if the reaction mixture has a sodium ionconcentration of greater than 3 wt. %, the reaction mixture is heated toabout 80° C. to about 85° C. and held at that temperature for anadditional hour and then cooled to about 60° C. and the concentration ofsodium ion in the liquid part of the reaction mixture is determined tobe less than or equal to 3 wt. % or the difference between the twotitrations values is less than or equal to 0.5 wt. %, the reaction iscomplete.

The reaction temperature can range from about 55° C. to refluxtemperature (e.g., 85° C.); preferably, about 85° C. The reactionmixture can be heated to about 85° C. and the aqueous strong base can beadded over from about 1 hour to about 3 hours; preferably, over about 2hours. Once the addition of the aqueous strong base is complete, thereaction mixture is heated for at least 30 additional minutes at about85° C. The reaction mixture can be heated for at least 30 additionalminutes or at least 1, at least 2, at least 3, at least 4, or at least 5additional hours. The reaction mixture can be cooled to about 60° C. andif the concentration of sodium ion in the liquid part of the reactionmixture is less than or equal to 3 wt. %, the reaction is complete.Alternatively, if the reaction mixture has a sodium ion concentration ofgreater than 3 wt. %, the reaction mixture is heated to about 85° C. andheld at that temperature for an additional hour and then cooled to about60° C. and the concentration of sodium ion in the liquid part of thereaction mixture is determined to be less than or equal to 3 wt. % orthe difference between the two titrations values is less than or equalto 0.5 wt. %, the reaction is complete.

The hydrolysis reaction can be monitored to determine when a desiredconversion has been reached, including substantially completeconversion. An in-process control allows for the control of reactionparameters, including reaction time and temperature, to controlconversion. For example, the hydrolysis reaction can be monitored bysampling an aliquot from the reaction mixture and titrating it against0.05M hydrochloric acid. If two consecutive titration values have adifference less than 0.55 wt. %, preferably, less than 0.5 wt. %, it maybe taken as an indication that the consumption of base in the reactionmixture reached a plateau and the concentration of the base remainsconstant. Also, it may be an indication that substantially all of themethyl ester groups in the polymer have been converted to carboxylategroups. The reaction time needed for the concentration of the base toreach a constant value can be used as an indication of having reachedthe end point of the hydrolysis reaction.

When the solid polymer content of the hydrolysis reaction is from about18 wt. % to about 22 wt. %, preferably, 20 wt. %, the reaction mixtureis titrated with hydrochloric acid and the reaction is consideredcomplete when the base concentration is less than or equal to about 4wt. %, preferably, 3 wt. %.

When the polymer solid content of the hydrolysis reaction is from about28 wt. % to about 32 wt. %, preferably, 30 wt. %, the reaction mixtureis titrated with hydrochloric acid and the reaction is consideredcomplete when the base concentration is less than or equal to about 6wt. %, preferably, 5 wt. %.

When the solid content of the hydrolysis reaction is from about 24 wt. %to about 28 wt. %, preferably, 24 wt. %, the reaction mixture istitrated with hydrochloric acid and the reaction is considered completewhen the base concentration is less than or equal to about 5 wt. %,preferably 4.5 wt. %.

The hydrolysis reaction can also be monitored by sampling a smallportion of the polymer, washing it with excess amount of water to removethe residual base, and extracting it with weak hydrochloric acid. Theextracted solution will contain the corresponding cation from the basebound to the polymer. The cation concentration in the extract isanalyzed by ion chromatography and calculated against the sample weight.The calculated cation weight concentration is a direct measurement ofthe degree of the progress of the hydrolysis reaction. The theoreticalcalculation of cation bound to fully hydrolyzed polymer is equal toabout 16 wt. % to about 19 wt. %, preferably, 19 wt. %, of total polymerweight.

The polymers having a pendant ester group used in the invention are inthe form of substantially spherical particles (i.e., beads or beadform). As used herein, the term “substantially” means generally roundedparticles having an average aspect ratio of about 1.0 to about 2.0.Aspect ratio is the ratio of the largest linear dimension of a particleto the smallest linear dimension of the particle. Aspect ratios may beeasily determined by those of ordinary skill in the art. This definitionincludes spherical particles, which by definition have an aspect ratioof 1.0. In some embodiments, the particles have an average aspect ratioof about 1.0, 1.2, 1.4, 1.6, 1.8 or 2.0. The particles may be round orelliptical when observed at a magnification wherein the field of view isat least twice the diameter of the particle.

The polymer particles have a mean diameter of from about 20 μm to about200 μm. Specific ranges are where the polymer particles have a meandiameter of from about 20 μm to about 200 μm, from about 20 μm to about150 μm, or from about 20 μm to about 125 μm. Other ranges include fromabout 35 μm to about 150 μm, from about 35 μm to about 125 μm, or fromabout 50 μm to about 125 μm. Particle sizes, including mean diameters,distributions, etc. can be determined using techniques known to those ofskill in the art. For example, U.S. Pharmacopeia (USP)<429> disclosesmethods for determining particle sizes.

The polymer particles can also have less than about 4 volume percent ofthe particles that have a diameter of less than about 10 μm;particularly, less than about 2 volume percent of the particles thathave a diameter of less than about 10 μm; more particularly, less thanabout 1 volume percent of the particles that have a diameter of lessthan about 10 μm; and even more particularly, less than about 0.5 volumepercent of the particles that have a diameter of less than about 10 μm.Specific ranges for particle size can be less than about 4 volumepercent of the particles that have a diameter of less than about 20 μm;less than about 2 volume percent of the particles that have a diameterof less than about 20 μm; less than about 1 volume percent of theparticles that have a diameter of less than about 20 μm; less than about0.5 volume percent of the particles that have a diameter of less thanabout 20 μm; less than about 2 volume percent of the particles that havea diameter of less than about 30 μm; less than about 1 volume percent ofthe particles that have a diameter of less than about 30 μm; less thanabout 0.5 volume percent of the particles that have a diameter of lessthan about 30 μm; less than about 2 volume percent of the particles thathave a diameter of less than about 40 μm; less than about 1 volumepercent of the particles that have a diameter of less than about 40 μm;or less than about 0.5 volume percent of the particles that have adiameter of less than about 40 μm.

The polymer having a pendant ester group can have a particle sizedistribution wherein not more than about 5 volume % of the particleshave a diameter less than about 30 μm (i.e., D(0.05)<30 μm), not morethan about 5 volume % of the particles have a diameter greater thanabout 250 μm (i.e., D(0.05)>250 μm), and at least about 50 volume % ofthe particles have a diameter in the range from about 70 to about 150μm.

The particle distribution of the polymer can be described as the span.The span of the particle distribution is defined as(D(0.9)−D(0.1))/D(0.5), where D(0.9) is the value wherein 90% of theparticles have a diameter below that value, D(0.1) is the value wherein10% of the particles have a diameter below that value, and D(0.5) is thevalue wherein 50% of the particles have a diameter above that value and50% of the particles have a diameter below that value as measured bylaser diffraction. The span of the particle distribution is typicallyfrom about 0.5 to about 1, from about 0.5 to about 0.95, from about 0.5to about 0.90, or from about 0.5 to about 0.85. Particle sizedistributions can be measured using Niro Method No. A 8 d (revisedSeptember 2005), available from GEA Niro, Denmark, using the MalvernMastersizer.

The polymer having a pendant ester of an acid group can be synthesizedin a suspension polymerization reaction by preparing an organic phaseand an aqueous phase. The organic phase typically contains a monomer ofFormula 11, a monomer of Formula 22, a monomer of Formula 33, and apolymerization initiator. The aqueous phase contains a suspensionstabilizer, a water soluble salt, water, and optionally a buffer. Theorganic phase and the aqueous phase are then combined and stirred undernitrogen. The mixture is generally heated to about 60° C. to about 80°C. for about 2.5 to about 3.5 hours, allowed to rise up to 95° C. afterpolymerization is initiated, and then cooled to room temperature. Aftercooling, the aqueous phase is removed. Water is added to the mixture,the mixture is stirred, and the resulting solid is filtered. The solidis washed with water, alcohol or alcohol/water mixtures.

Polymerization suspension stabilizers, such as polyvinyl alcohol, can beused to prevent coalescence of particles during the polymerizationprocess. Further, it has been observed that the addition of sodiumchloride in the aqueous phase decreased coalescence and particleaggregation. Other suitable salts for this purpose include salts thatare soluble in the aqueous phase. Preferably, these water soluble saltsare added at a concentration of from about 0.1 wt. % to about 10 wt. %,particularly from about 2 wt. % to about 5 wt. % and even moreparticularly from about 3 wt. % to about 4 wt. %.

Preferably, an organic phase of methyl 2-fluoroacrylate (90 wt. %),1,7-octadiene (5 wt. %) and divinylbenzene (5 wt. %) is prepared and 0.5wt. % of lauroyl peroxide is added to initiate the polymerizationreaction. Additionally, an aqueous phase of water, polyvinyl alcohol,phosphates, sodium chloride, and sodium nitrite is prepared. Undernitrogen and while keeping the temperature below about 30° C., theaqueous and organic phases are mixed together. Once mixed completely,the reaction mixture is gradually heated with continuous stirring. Afterthe polymerization reaction is initiated, the temperature of thereaction mixture is allowed to rise up to about 95° C. Once thepolymerization reaction is complete, the reaction mixture is cooled toroom temperature and the aqueous phase is removed. The solid can beisolated by filtration after water is added to the mixture. Theresulting product is a crosslinked (methyl2-fluoroacrylate)-divinylbenzene-1,7-octadiene terpolymer.

Having described the invention in detail, it will be apparent thatmodifications and variations are possible without departing from thescope of the invention defined in the appended claims.

EXAMPLES

The following non-limiting examples are provided to further illustratethe present invention.

Hydrolysis Procedure 1

Hydrolysis of cross-linked methylfluoroacrylate polymer (Sample 1-Me)was done in library format. Cross linked methylfluoroacrylate polymer(Sample 1-Me) was prepared by polymerization of methyl 2-fluoroacrylatewith 1,7-octadiene and divinylbenzene, as disclosed in U.S. Ser. No.12/545,810 (published as US Patent Application Publication No.2010/0111891), for example as in Example 8, Part A up to the hydrolysisstep in paragraph

U.S. Patent Application Publication No. 2010/0111891 is incorporatedherein by reference for all purposes. Sample 1-Me (1.3 g, 11.1 mmole)was charged into 8 mL vials. Solvent water (3.5 g) and sodium hydroxide(NaOH, 2.1 g, 13.6 mmole, 25 wt. % in water) were dispensed usingautomated liquid dispensing robots. Vials were placed in a Biotagereactor (Endeavor series) and sealed. The reaction mixture was stirredwith an overhead stirrer and purged with inert gas for 15 minutes priorto heating to 83° C. for a particular reaction time. Samples were thencollected by parallel filtration. The supernatant solution fromindividual reaction was collected and the filter cake was washed withdistilled water until all the residual base was washed away. Thesupernatant solution was titrated against 0.05 M hydrochloric acid tomeasure the residual sodium hydroxide left in the reaction mixture. Atitration weight percent value of less than 3 wt. % sodium hydroxide wasan indication of complete hydrolysis. The hydrolyzed polymer wasextracted with acidic solution to measure the amount of sodium (Na⁺)incorporated in the polymer as a measure of degree of completehydrolysis. A measurement of 17-18 wt. % of Na⁺ in the polymer wasindicative of complete hydrolysis. The samples 2-A1 to 2-A8 report theresults of these experiments.

Hydrolysis Procedure 2

Hydrolysis of methylfluoroacrylate polymer (Sample 1-Me) was done inlibrary format. Methylfluoroacrylate polymer (Sample 1-Me) (1.3 g, 11.1mmole) was charged into 8 mL vials. Solvent water (3.0 g), methanol(0.51 g, d: 0.791) and sodium hydroxide (NaOH, 2.1 g, 13.6 mmole, 25 wt.% in water) were dispensed using automated liquid dispensing robots.Vials were placed in a Biotage reactor (Endeavor series) and sealed. Thereaction mixture was stirred with an overhead stirrer and purged withinert gas for 15 minutes prior to heating to 83° C. for a particularreaction time. Samples were then collected by parallel filtration. Thesupernatant solution from individual reaction was collected and thefilter cake was washed with distilled water until all the residual basewas washed away. The supernatant solution was titrated against 0.05 Mhydrochloric acid (HCl) to measure the residual sodium hydroxide left inthe reaction mixture. A titration weight percent value of less than 3wt. % sodium hydroxide was an indication of complete hydrolysis. Thehydrolyzed polymer was extracted with acidic solution to measure theamount of sodium (Na⁺) incorporated in the polymer as a measure ofdegree of complete hydrolysis. A measurement of 17-18 wt. % of Na⁺ inthe polymer was indicative of complete hydrolysis. The samples 3-A1 to3-A8 report the results of these experiments.

Hydrolysis Procedure 3

Hydrolysis of methylfluoroacrylate polymer (Sample 1-Me) was done inlibrary format. Methylfluoroacrylate polymer (Sample 1-Me) (1.3 g, 11.1mmole) was charged into 8 mL vials. Solvent water (2.2 g), methanol(0.30 g, d: 0.791) and sodium hydroxide (NaOH, 1.1 g, 13.6 mmole, 50 wt.% in water) were dispensed using automated liquid dispensing robots.Vials were placed in a Biotage reactor (Endeavor series) and sealed. Thereaction mixture was stirred with an overhead stirrer and purged withinert gas for 15 minutes prior to heating to 83° C. for a particularreaction time. Samples were then collected by parallel filtration. Thesupernatant solution from individual reaction was collected and thefilter cake was washed with distilled water until all the residual basewas washed away. The supernatant solution was titrated against 0.05 Mhydrochloric acid (HCl) to measure the residual NaOH left in thereaction mixture. A titration weight percent value of less than 5 wt. %sodium hydroxide was an indication of complete hydrolysis. Thehydrolyzed polymer was extracted with acidic solution to measure theamount of sodium (Na⁺) incorporated in the polymer as a measure ofdegree of complete hydrolysis. A measurement of 17-18 wt. % of Na⁺ inthe polymer was indicative of complete hydrolysis. The samples 4-A1 to4-A8 report the results of these experiments.

Hydrolysis Procedure 4

Hydrolysis of methylfluoroacrylate polymer (Sample 1-Me) was done inlibrary format. Methylfluoroacrylate polymer (Sample 1-Me) (1.3 g, 11.1mmole) was charged into 8 mL vials. Solvent water (3.0 g), methanol(0.51 g, d: 0.791) and sodium hydroxide (NaOH, 2.1 g, 13.6 mmole, 25 wt.% in water) were dispensed using automated liquid dispensing robots.Vials were placed in a Biotage reactor (Endeavor series) and sealed. Thereaction mixture was stirred with an overhead stirrer and purged withinert gas for 15 minutes prior to heating. Vials in this library wereheated to a different temperature (from 60° C. to 90° C.) for aparticular reaction time. Samples were then collected by parallelfiltration. The supernatant solution from individual reactions wascollected and the filter cake was washed with distilled water until allthe residual base was washed away. The supernatant solution was titratedagainst 0.05 M hydrochloric acid (HCl) to measure the residual sodiumhydroxide left in the reaction mixture. A titration weight percent valueof less than 3 wt. % sodium hydroxide was an indication of completehydrolysis. The hydrolyzed polymer was extracted with acidic solution tomeasure the amount of sodium (Na⁺) incorporated in the polymer as ameasure of degree of complete hydrolysis. A measurement of 17-18 wt. %of Na⁺ in the polymer was indicative of complete hydrolysis. The samples5-A1 to 5-A8 report the results of these experiments.

NaOH NaOH NaOH Na⁺ Co- 25 50 Reaction wt. % wt % in 1- Solvent Solventwt. % wt. % Reaction temper- in the polymer Me Water MeOH soln soln timeature Super- after Sample (g) (g) (g) (g) (g) (h) (° C.) natanthydrolysis 2-A1 1.3 3.5 0 2.1 5 83 7.62 8.35 2-A2 1.3 3.5 0 2.1 7 835.77 11.88 2-A3 1.3 3.5 0 2.1 9 83 4.18 16.16 2-A4 1.3 3.5 0 2.1 11 833.29 16.63 2-A5 1.3 3.5 0 2.1 13 83 2.75 17.93 2-A6 1.3 3.5 0 2.1 15 832.66 17.83 2-A7 1.3 3.5 0 2.1 17 83 2.45 17.56 2-A8 1.3 3.5 0 2.1 20 832.64 17.57 3-A1 1.3 3.0 0.51 2.1 1 83 6.88 8.56 3-A2 1.3 3.0 0.51 2.1 283 2.89 16.72 3-A3 1.3 3.0 0.51 2.1 3 83 3.01 16.87 3-A4 1.3 3.0 0.512.1 4 83 2.63 17.22 3-A5 1.3 3.0 0.51 2.1 5 83 2.53 17.12 3-A6 1.3 3.00.51 2.1 6 83 2.40 17.12 3-A7 1.3 3.0 0.51 2.1 7 83 2.62 17.43 3-A8 1.33.0 0.51 2.1 8 83 2.45 17.4 4-A1 1.3 2.2 0.30 1.1 1 83 12.024 7.26 4-A21.3 2.2 0.30 1.1 2 83 5.278 16.77 4-A3 1.3 2.2 0.30 1.1 3 83 4.956 16.924-A4 1.3 2.2 0.30 1.1 4 83 4.627 17.19 4-A5 1.3 2.2 0.30 1.1 5 83 4.3117.18 4-A6 1.3 2.2 0.30 1.1 6 83 4.452 17.50 4-A7 1.3 2.2 0.30 1.1 7 834.202 17.53 4-A8 1.3 2.2 0.30 1.1 8 83 4.353 17.24 5-A1 1.3 3.0 0.51 2.18 60 8.99 2.48 5-A2 1.3 3.0 0.51 2.1 8 65 8.48 3.50 5-A3 1.3 3.0 0.512.1 8 70 7.79 5.43 5-A4 1.3 3.0 0.51 2.1 8 75 4.85 12.58 5-A5 1.3 3.00.51 2.1 8 80 2.68 17.18 5-A6 1.3 3.0 0.51 2.1 8 85 2.35 17.52 5-A7 1.33.0 0.51 2.1 14 75 5.06 12.09 5-A8 1.3 3.0 0.51 2.1 20 75 4.54 13.62Hydrolysis Procedure 5

To a reactor equipped with an overhead stirrer and condenser, 20 kg ofSample 1-Me polymer in methyl ester form was charged. Methanol (7.91 kg)and water (46.3 kg) were then added to the Sample 1-Me sample. Theresulting mixture was stirred at 180 rpm and purged with nitrogen gasfor 30-45 minutes prior to heating. The reaction assembly was heated to83° C. under a nitrogen blanket. When the temperature of the reactionmixture reached 83° C., sodium hydroxide (NaOH, 26.53 L, 0.208 moles, 25wt. % in water, d, 1.26) was added slowly over a 2 hour period. Themolar ratio of the base to the methyl ester monomer in the Sample 1-Mepolymer was 1.22. The heating continued after the addition of sodiumhydroxide solution for an additional 2.5 hours. Thus, the total heatingtime was 4.5 hours, the reactor was subsequently cooled to 60° C. in 2hours, to reach the first in process control (IPC) point.

The reaction end point was determined by sampling a 200 μl aliquot fromthe reaction mixture at the 4.5 hour mark and 60 minutes thereafter. Theextracted sample passed through 1.0 μm filter disc and then was titratedagainst 0.05 M HCl solution. The sodium hydroxide content in thesupernatant as determined by titration was found to be below 3 wt. %(measured 2.6 wt. %). When two successive samples were within 0.5 wt. %in sodium ion content from each other the reaction was determined to becomplete.

The reaction mixture was allowed to cool down to ambient temperature andthe hydrolyzed product was collected by filtration. The filtered cakewas washed with distilled water until the pH was 7. The filtered cakewas lyophilized for 48 hours.

Hydrolysis Procedure 6

To a reactor equipped with an overhead stirrer and condenser, 20 g ofSample 1-Me polymer in methyl ester form was charged. Methanol (4.56 g)and water (32.69 g) were then added to the Sample 1-Me sample. Theresulting mixture was stirred at 180 rpm and purged with nitrogen gasfor 30-45 minutes prior to heating. The reaction assembly was heated to83° C. under a nitrogen blanket. When the temperature of the reactionmixture reached 83° C., sodium hydroxide (NaOH, 11.03 L, 0.208 mmoles,50 wt. %, d, 1.51) was added slowly over a 2 hour period. The molarratio of base to the methyl ester monomer in the 1-Me polymer was 1.22.The heating continued after the addition of sodium hydroxide solutionfor an additional 2.5 hours. Thus, the total heating time was 4.5 hours.The reactor was subsequently cooled to 60° C. in 2 hours, to reach thefirst IPC point.

The reaction end point was determined by sampling 200 μl aliquot fromthe reaction mixture at the 4.5 hour mark and 60 minutes thereafter. Theextracted sample passed through 1.0 μm filter disc and then was titratedagainst 0.05 M HCl solution. The sodium hydroxide content in thesupernatant as determined by titration was found to be below 5 wt. %(measured 4.65 wt. %). When two successive samples were within 0.5 wt. %in sodium ion content from each other the reaction was determined to becomplete.

The reaction mixture was allowed to cool down to ambient temperature andthe hydrolyzed product was collected by filtration. The filter cake waswashed with distilled water until the pH was 7. The filter cake waslyophilized for 48 hours.

In view of the above, it will be seen that the several objects of theinvention are achieved and other advantageous results attained.

As various changes could be made in the above polymers, pharmaceuticalcompositions, and methods of treatment without departing from the scopeof the invention, it is intended that all matter contained in the abovedescription shall be interpreted as illustrative and not in a limitingsense.

What is claimed is:
 1. A process for converting an ester group of apolymer to an acid group comprising: forming a reaction mixture being anaqueous suspension and having a substantially oxygen-free atmosphere,the reaction mixture comprising an aqueous strong base solution and apolymer having a pendant ester of an acid group which hydrolyzes toproduce a polymer comprising the pendant acid group or a salt thereofand an alcohol, wherein the polymer having a pendant ester of an acidgroup is in a bead form and the reaction mixture comprises at least 5 kgof a polymer having a pendant ester of an acid group.
 2. The process ofclaim 1, wherein the reaction mixture is allowed to react for up to 14hours.
 3. The process of claim 1, wherein the reaction mixture isallowed to react for up to 10 hours.
 4. The process of claim 3, whereinthe reaction mixture is allowed to react for up to about 6 hours.
 5. Theprocess of claim 3, wherein the reaction mixture is allowed to react forup to about 5 hours.
 6. The process of claim 4, wherein the reactionmixture comprises at least 10 kg of a polymer having a pendant ester ofan acid group.
 7. The process of claim 4, wherein the polymer having apendant ester of an acid group is a hydrophobic polymer.
 8. The processof claim 1, wherein the polymer having a pendant ester of an acid groupis crosslinked.
 9. The process of claim 1, wherein the polymer having apendant ester of an acid group comprises structural units correspondingto Formulae 1 and 2, Formulae 1 and 3, or Formulae 1, 2, and 3, whereinFormula 1, Formula 2, and Formula 3 are represented by the followingstructures:

wherein R₁ and R₂ are each independently hydrogen, alkyl, cycloalkyl, oraryl; A₃₁ is an ester of a carboxylic, phosphonic, or phosphoric group;X₁ is arylene; and X₂ is alkylene, an ether moiety, or an amide moiety.10. The process of claim 1, wherein the polymer having a pendant esterof an acid group comprises structural units corresponding to Formulae1A, 2A, and 3A represented by the following structures:


11. The process of claim 1, wherein the polymer having a pendant esterof an acid group comprises a reaction product of a polymerizationmixture comprising monomers of either (i) Formulae 11 and 22, (ii)Formulae 11 and 33, or (iii) Formulae 11, 22, and 33, wherein Formula11, Formula 22, and Formula 33 are represented by the followingstructures:

and wherein R₁ and R₂ are each independently hydrogen, alkyl,cycloalkyl, or aryl; A₃₁ is an ester of a carboxylic, phosphonic, orphosphoric acid group; X₁ is arylene; and X₂ is alkylene, an ethermoiety, or an amide moiety.
 12. The process of claim 1, wherein thepolymer having a pendant ester of an acid group comprises a reactionproduct of a polymerization mixture comprising monomers of Formulae 11,22, and 33 and Formulae 11, 22, and 33 are represented by the followingstructures:


13. The process of claim 12, wherein the alkyl group of the ester is amethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,sec-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-1-butyl,3-methyl-1-butyl, 3-methyl-2-butyl, 2,2-dimethyl-1-propyl,1,1-dimethyl-1-propyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-1-pentyl,2-methyl-2-pentyl, 2-methyl-3-pentyl, 3-methyl-1-pentyl,3-methyl-2-pentyl, 3-methyl-3-pentyl, 4-methyl-1-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 2,3-dimethyl-1-butyl,3,3-dimethyl-1-butyl, 3,3-dimethyl-2-butyl, 2,3-dimethyl-2-butyl, or2-ethyl-1-butyl.
 14. The process of claim 7, wherein the hydrophobicpolymer having a pendant ester of an acid group comprises a methyl esterof poly-α-fluoroacrylic acid, the methyl ester of poly-α-fluoroacrylicacid is crosslinked with a crosslinking monomer, and the crosslinkingmonomer is divinyl benzene, 1,7-octadiene, or a combination thereof. 15.The process of claim 1, wherein the polymer content of an aqueoussuspension of the polymer having a pendant ester of an acid group addedto the reaction mixture is about 15 wt. % to about 30 wt. %.
 16. Theprocess of claim 15, wherein the concentration of the aqueous strongbase solution added to the reaction mixture is about 15 wt. to about 50wt. %.
 17. The process of claim 16, wherein the concentration of theaqueous strong base solution added to the reaction mixture is about 10mol % to about 20 mol %.
 18. The process of claim 1, wherein the aqueousstrong base solution further comprises an alcohol at a concentrationfrom about 5 wt. % to about 25 wt. %.
 19. The process of claim 17,wherein the aqueous strong base solution further comprises an alcohol ata concentration from about 5 wt. % to about 25 wt. %.
 20. The process ofclaim 1, wherein the oxygen-free atmosphere comprises an inert gas andthe inert gas is helium, neon, nitrogen, argon, krypton, xenon, or acombination thereof.
 21. The process of claim 17, wherein thetemperature of the reaction mixture is about 55° C. to about 95° C.